The present invention relates generally to the uncoupling of sugar-mediated coupling of proteins, lipids, nucleic acids, and other biomaterials, and any combination thereof, resulting from their reaction with glucose and other reducing sugars. The reaction between glucose and protein amino groups was studied in detail by Maillard in 1912, who observed that glucose or other reducing sugars react with amino acids to form adducts that undergo a series of dehydrations and rearrangements to form stable brown pigments. Further studies have suggested that stored and heat treated foods undergo nonenzymatic browning as a result of the reaction between glucose and the polypeptide chain, and that the proteins are resultantly cross-linked and correspondingly exhibit decreased bioavailability. U.S. Pat. No. 6,007,865 discloses that these reactions occur in vivo at normal glucose levels. U.S. Pat. No. 6,007,865 further terms these reactions as advanced glycosylation (or glycation) end products (AGEs).
Several therapeutic approaches have been attempted based upon intervening in the accumulation of AGEs in vivo. One approach, exemplified in U.S. Pat. No. 4,758,583, concerns the inhibition of the formation of AGEs from their precursors, by the administration of agents such as aminoguanidine and related compounds. By reacting with an early glycosylation product that results from the original reaction between the target protein and glucose, this patent discloses that these agents block the formation of AGEs and further formation of AGEs and cross-links in tissues is inhibited
U.S. Pat. Nos. 5,656,261, 5,853,703, 6,007,865, and 6,121,300, and in P.C.T. Intl. Appl. WO97/42175, disclose agents and methods that reverse (also termed cleave or break) existing AGE cross-links in vitro and in vivo. Specifically, these patents disclose a mechanism of protein crosslinking by sugars, involving formation of a 6-hydroxy-2,3-hexanedione protein-protein cross-linking structure which has an epsilon amino group of one protein attached to the 1 position, and a nucleophilic side chain of another protein attached to the 5 position. Further, these patents disclosed compounds such as 4,5-dimethyl-3-(2-oxo-2-phenylethyl)thiazolium bromide, which were claimed to have broken protein-protein cross-links in a manner consistent with a mechanism involving transient formation of a carbanion by deprotonation of the unsubstituted 2-position of the thiazolium ring, followed by attack of the carbanion at one of the ketone carbonyls of the hypothetical 6-hydroxy-2,3-hexanedione protein-protein cross-linking structure. Subsequent rearrangements known for such thiazolium adducts could lead to cleavage of the bond between the carbonyl carbons, resulting in formation of an aldehyde fragment and a carboxylic acid fragment.
In one embodiment of the present invention, compositions and methods are disclosed for uncoupling of sugar-mediated coupling of proteins, lipids, nucleic acids, and other biomaterials, and any combination thereof. In another embodiment, sugar-mediated coupling caused by other reactive sugars present in vivo or in foodstuffs, including ribose, galactose and fructose may also be uncoupled by the methods and compositions of the present invention. The compositions and methods comprise the below disclosed compounds.
In another embodiment, the compositions have utility in vivo to reduce the deleterious effects of sugar-mediated coupling processes in an organism, when the organism is exposed to the compound or composition internally, by ingestion, transdermal application, or other means. The compositions comprise the below disclosed compounds
In yet another embodiment, the compositions are useful for the ex-vivo treatment of organs, cells and tissues and external treatment of hair, nails and skin to rejuvenate them by changing deformability and increase the tissue diffusion coefficient. This treatment is accomplished by bathing or perfusing the biological material outside of the body. The compositions comprise the below disclosed compounds.
In still another embodiment, the compositions have utility in treatment of proteinaceous organism-derived materials of commerce comprising fur, leather, feathers, down, silk, wool, gut, or the like, to enhance their softness and suppleness of texture and reduce their stiffness and brittleness, thus increasing the value and functionality of such materials. Such treatment is accomplished by exposing the organism-derived material to the composition or a solution of the composition in water or other suitable vehicle.
In a further embodiment, the present invention relates to the above-identified compositions that comprises one or more compounds of thiazole derivatives where carbon substituents are attached to the 2 position of the thiazolium nucleus and represented by formula (I): 
wherein R1 is a C1-C18 alkyl group, or the group xe2x80x94CH(R5)xe2x80x94OH, or the group xe2x80x94CH(R5)xe2x80x94OC(xe2x95x90O)xe2x80x94R6 wherein R5 is a C1-C18 alkyl group and R6 is selected from the group consisting of C1-C18 alkyl, phenyl, halosubstituted phenyl, C1-C18 alkoxysubstituted phenyl and naphthyl;
R2 is selected from the group consisting of hydroxy, phenyl, halosubstituted phenyl, C1-C18 alkoxysubstituted phenyl, a C5-7 aromatic, unsaturated or saturated heterocyclic ring having one to three heteroatoms selected from the group consisting of N, O and S;
R3 and R4 are independently selected from the group consisting of hydrogen, C1-C18 alkyl or hydroxyalkyl, or phenyl, or R3 and R4 together are a bridge of 3-6 methylene units, or R3 and R4 together with their ring atoms may be an aromatic ring system of 6-10 carbons, optionally substituted with one or more halo, lower alkyl, lower alkoxy, or amino groups; and
Xxe2x88x92 is halide, preferably chloride or bromide, or other pharmaceutically acceptable anion.
Certain compounds of formula (I) may undergo cycloelimination to form lactones or cyclic enol ethers constituting novel thiazolooxazinium derivatives which are also embodiments of this invention.
In a further embodiment the present invention relates to novel compounds of formula: 
wherein
R1 is hydrogen, or xe2x80x94C(xe2x95x90O)xe2x80x94R6 wherein R6 is selected from the group consisting of C1-C18 alkyl, C1-C18 alkoxy, phenyl, halosubstituted phenyl, C1-C18 alkoxysubstituted phenyl and naphthyl;
R1 is hydrogen, phenyl or a C1-5 alkyl group;
R3 and R4 are independently selected from the group consisting of hydrogen, C1-C18 alkyl or hydroxyalkyl, or phenyl, or R3 and R4 together are a bridge of 3-6 methylene units, or R3 and R4 together with their ring atoms may be an aromatic ring system of 6-10 carbons, optionally substituted with one or more halo, lower alkyl, lower alkoxy, or amino groups; and
Xxe2x88x92 is mesitylene-2-sulfonate or other pharmaceutically acceptable anion.
In another embodiment the present invention relates to the above-identified compositions that comprise one or more compounds of naphthothiazole derivatives of formula (II): 
xe2x80x83wherein
R1 is selected from the group consisting of H, C1-5 lower alkyl, C1-18 lower alkanoyl, and aroyl;
R2 is selected from the group consisting of hydrogen and C1-5 lower alkyl;
R3 is selected from the group consisting of lower alkyl, C3xe2x80x94C8 cycloalkyl, phenyl, 1-[(aminoiminomethyl)hydrazono]ethyl substituted phenyl, naphthyl, or aminoalkyl of structure: 
xe2x80x83wherein R7 and R8 are independently selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 hydroxyalkyl, or R7 and R8 taken together with the nitrogen atom form a C4-C7 heterocyclic ring optionally containing one or two additional heteroatoms selected from the group consisting of N, O or sulfur;
R4is selected from the group consisting of methyl, lower alkyl, or aminoalkyl of structure 
xe2x80x83wherein R9 and R10 are independently selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 hydroxyalkyl, or R9 and R10 taken together with the nitrogen atom form a C4-C7 heterocyclic ring optionally containing one or two additional heteroatoms selected from the group consisting of N, O or sulfur; and
R5 is selected from the group consisting of hydrogen, acetyl and 1-[(aminoiminomethyl)-hydrazono]ethyl; or hydrochloride salts thereof, or other pharmaceutically acceptable salts thereof.
In a further embodiment, the present invention relates to the above-identified compositions that comprises one or more compounds of pyridinium and pyrimidinium derivatives of formula (III): 
wherein A is hydrogen, cyano, or a C6-C10 aryl group, said aryl groups optionally substituted by one or more lower alkyl, lower alkoxy, or halo groups;
Z is CH or N;
R1 is hydroxy, C1-C18 alkoxy, amino optionally substituted with 1-2 independent C1-C18 alkyl groups, phenyl, halosubstituted phenyl, C1-C18 alkoxysubstituted phenyl, or a C4-7 aromatic or unsaturated or saturated heterocyclic ring having one to three heteroatoms selected from the group consisting of N, O, or S, with the proviso that at least one heteroatom is nitrogen and said nitrogen is directly bonded to the carbonyl group; and
R2 and R3 are independently selected from hydrogen, amino, or C1-C18 alkyl groups, or R2 and
R3 taken together may form a carbocyclic or heterocyclic ring, and
Xxe2x88x92 is halide, preferably chloride or bromide, or other pharmaceutically acceptable anion.
In another embodiment, the present invention relates to the above-identified compositions that comprises one or more compounds of 1-aminopyrimidinium derivatives of formula (IV): 
wherein R1 is selected from:
amino,
methyl,
cyanomethyl,
the group xe2x80x94CH2xe2x80x94A where A is a C6-C10 aryl group optionally substituted by one or more lower alkyl, lower alkoxy or halo groups, or
the group xe2x80x94CH2xe2x80x94C(xe2x95x90O)xe2x80x94Z where Z is selected from hydroxy, C1-C18 alkoxy, amino optionally substituted with 1-2 C1-C18 alkyl groups, a C6-C10 aryl group optionally substituted by one or more lower alkyl or halo groups, or a C4-7 aromatic or unsaturated or saturated heterocyclyl group having one to three heteroatoms selected from the group consisting of N, O, or S;
R2 and R3 are independently selected from hydrogen, amino, lower alkoxy, or C1-C8 alkyl groups, or if R2 and R3 are on adjacent atoms then R2 and R3 taken together with their ring atoms may form a fused carbocyclic or heterocyclic ring; and
Xxe2x88x92 is mesitylene-2-sulfonate or other pharmaceutically acceptable anion.
In yet another embodiment, the present invention relates to the above-identified compositions that comprises one or more compounds of imidazolium derivatives of formula (V): 
wherein R1 and R2 are independently selected from hydroxy, lower alkoxy, amino optionally substituted with 1-2 lower alkyl groups, aryl, halosubstituted aryl, (lower alkyl)substituted aryl, or a C5-7 unsaturated or saturated heterocyclic ring having one to three heteroatoms selected from the group consisting of N, O, and S and Xxe2x88x92 is halide, preferably chloride or bromide, or other pharmaceutically acceptable anion.
The ability of the compositions of the present invention to uncouple sugar-mediated coupling of proteins, lipids, nucleic acids, and other biomaterials, and any combination thereof carries with it significant implications in all applications where sugar-mediated coupling is a serious detriment. In the area of food technology, for instance, the uncoupling of sugar-mediated coupling would confer a reduction of the increased toughness resulting from the formation of sugar-mediated coupling during storage. In yet another embodiment, the application of the composition of the present invention has particular benefit in vivo as sugar-mediated coupling may adversely affect several of the significant protein masses or other biomaterials of the body, among them collagen, elastin, lens proteins, the kidney glomerular basement membrane, nucleic acids and lipids. These proteins or other biomaterials deteriorate both with age (hence the application of the term xe2x80x9cprotein agingxe2x80x9d) and more rapidly as a consequence of diabetes. Accordingly, the ability to uncouple sugar mediated coupling of proteins, lipids, nucleic acids, and other biomaterials, and any combination thereof in the body provides for treatment of the complications of diabetes and aging for instance, or ex-vivo treatment of transplantable organs as another instance, or external treatment of hair, skin and nails as yet another instance, and thereby improving the quality and, perhaps, duration of animal and human life.